tbuckley/cabot-search huggingface dataset:
Identification of lineage-specific transcription factor defined subtypes in small cell/neuroendocrine bladder cancer.
Authors: Woonyoung Choi, Mingxiao Feng, Gabriel Epstein, Jean H. Hoffman-Censits, Max R. Kates, Bogdan Czerniak, Eva Comperat, Andres Matoso, Seungchan Kim, David James McConkey
Journal: Journal of Clinical Oncology (2023)

568 Background: Small cell/neuroendocrine bladder cancer (SCBC) is a rare and clinically aggressive disease. However, its molecular characteristics are poorly studied; hence, biology-based therapeutic options are not available. Strong pan-cancer similarity in gene expression signature of neuroendocrine (NE) tumors including SCBC and small cell lung cancer (SCLC) has been reported. Recent genomics studies discovered that SCLC can be grouped into lineage- specific transcription factor (TF)-defined subtypes. Therefore, we explored whether TF-defined molecular subtypes could also be observed in SCBC with the goal of developing subtype-specific therapeutic strategies. Methods: Whole transcriptome RNAseq on a cohort of n = 44 pure SCBCs collected at Johns Hopkins (n=20) and Tenon Hospital (Paris) (n=24) and DNA panel sequencing on subset of the tumors (n=24) were performed. Two expert genitourinary pathologists selected the cases for the analyses based on the histopathological characteristics of the tumor tissue. Results: SCBC tumors displayed overexpression of canonical NE markers and high mutation rates in TERT, TP53 and RB1 with 92%, 75% and 38%, respectively, confirming the concordance between genomic features and histopathologic characteristics.Lineage-specific TFs (ASCL1, NEUROD1, and POU2F3) defined three molecular subtypes of SCBC that resembled the previously reported SCLC subtypes. The three subtypes expressed variable levels of NE biomarkers and were heterogeneous with respect to distinct downstream therapeutic targets. The ASCL1 and NEUROD1 subtypes expressed the highest levels of NE lineage-specific gene expression and were associated with expression of known regulators of the neuroendocrine phenotype including FOXA2 and HES6, respectively. The ASCL1 subtype was also enriched with DLLs and other genes that control oncogenic Notch signaling, whereas tumors enriched with POU2F3, a master regulator of the NE-low SCBC subtype, expressed TRPM5, SOX9 and CHAT. Finally, an inverse association between NE lineage-specific gene expression and immune signatures associated with response to immunotherapy was observed. Conclusions: Three lineage-specific TFs (ASCL1, NEUROD1, and POU2F3) defined discrete molecular subtypes in SCBC. Each subtype was characterized by distinct therapeutic targets and gene expression signatures associated with response to immunotherapy. Future studies will be required to test the clinical relevance of these observations.
<sup>68</sup>GaPSMA-11 PET/CT to monitor treatment response in patients with metastatic prostate cancer: The concordance between biochemical response and PSMA response.
Authors: Baris Esen, Hulya Seymen, Kayhan Tarim, Ersin Köseoğlu, Yasemin Bolukbasi, Okan Falay, Mehmet Onur Demirkol, Derya Tilki, Tarik Esen
Journal: Journal of Clinical Oncology (2023)

49 Background: The aim of this study was to assess whether PSMA PET is associated with flares, with discordant results in regard to biochemical response, and with positivity rates at low PSA values while monitoring metastatic prostate cancer (mPCa) receiving systemic treatment. Methods: A total of 96 patients with PSMA PET-detected mPCa who underwent at least one follow-up scan after receiving systemic treatment were included in the study. PSA levels at baseline PSMA PET-CT (bPSMA) and follow-up PSMA PET scans (fPSMA) were recorded. Any significant PSMA uptake at prostate and/or metastatic lesions were considered PSMA positivity. PSMA response were decided according to PSMA PET Progression (PPP) criteria . Biochemical progression was defined as ≥25% increase in PSA (1 ng/dL was the minimal starting value). PSMA PET and PSA response were dichotomized into progressive disease (PD) vs non-PD. Discordant responses among different metastases and prostate were defined as the condition when some metastatic lesions (or prostate) are responding (CR or PR) to systemic treatment while others had progressed. Results: A total of 346 serial PSMA PET/CT (96 bPSMA and 249 fPSMA) scans were evaluated. The median time between consecutive PSMA PET scans was 6.3 months (IQR: 4.7 – 10.6) Overall PSMA PET positivity rate of fPSMA scans was 88.4% (220/249). PSMA positivity rates according PSA levels were summarized. PPP was detected in 93 cases (37.8%) and biochemical progression was observed in 73 cases (30.2%). PSA and PSMA responses were highly concordant (Cohen’s K=0.623, p&lt;0.001). PSA-PSMA discordant responses were detected in 39 scans (17%). The possible causes could be identified in 34 of 39 scans (87%) while no obvious reason for discordance could be shown in the remaining 5. Conclusions: PSMA PET/CT showed very high detection rates of malignant lesions even in very low PSA values when monitoring treatment response in patients receiving systemic treatment for mPCa. PSA and PSMA responses were highly concordant. In cases with discordance, the reason seems to be the discordant behaviour of intraprostatic and metastatic lesions and not necessarily PSMA flares. PSMA PET is a promising biomarker to assess treatment response in patients with mPCa. [Table: see text]
Association of intermittent or continuous androgen deprivation therapy with cardiovascular disease and endocrine/metabolic disorders in patients with nonmetastatic prostate cancer.
Authors: Alicia K. Morgans, Ramin Ebrahimi, Priyanka J. Bobbili, Esmond Nwokeji, Raj Gandhi, Raj Desai, Adina Zhang, Michael Ryan, Sarah Hanson, Mei Sheng Duh, Mark A. Preston
Journal: Journal of Clinical Oncology (2023)

83 Background: Evidence on risks of cardiovascular disease (CVD) and endocrine/metabolic disorders associated with long-term intermittent and continuous androgen deprivation therapy (iADT and cADT, respectively) in patients (pts) with nonmetastatic prostate cancer (nmPC) is mixed. This real-world study examined these risks in pts with nmPC receiving iADT or cADT in the US. Methods: This was a retrospective cohort study of SEER-Medicare pts with nmPC initiating ADT (2010–2017), with ≥36 months of continuous insurance coverage, unless death occurred, and who did not receive chemotherapy or a second-generation anti-androgen during follow-up. iADT and cADT cohorts were defined by treatment patterns and gaps in therapy. Comorbidities and clinical events were identified using ICD-9/10-CM codes. Outcomes examined were major adverse cardiovascular events (MACE [myocardial infarction (MI), stroke, cardiomyopathy/heart failure (HF), pulmonary embolism (PE), ischemic heart disease (IHD), or all-cause mortality]) and endocrine/metabolic events (diabetes, hypercholesterolemia, bone fractures, or osteoporosis). Inverse probability of treatment-weighted Cox regression models estimated the adjusted hazard ratio (aHR) of the outcomes. Subgroup analyses examined pts by CVD history. A sensitivity analysis restricted the definition of MACE to include CVD-related mortality as a component, i.e., MACE SA (MI, stroke, cardiomyopathy/HF, PE, IHD, or CVD-related mortality). Results: 10,655 pts were included; 2095 (20%) received iADT and 8560 (80%) cADT; 63% of iADT pts and 66% of cADT pts had baseline CVD history. Median follow-up was 44 and 48 months and time on ADT (excluding gaps for iADT pts) was 23 and 17 months for the iADT and cADT cohorts, respectively. In adjusted analyses, pts receiving cADT had a lower risk of MACE vs iADT. No difference in risk of endocrine/metabolic events was observed. Results for MACE were similar in pts with prior CVD history; however, there was no difference in risk of MACE in those without CVD history. Sensitivity analysis results for MACE SA were similar to the main results. Conclusions: Pts with nmPC receiving cADT had a lower risk of MACE, and no difference in risk of endocrine/metabolic events, compared with iADT. There was no difference in risk of MACE in pts without a prior history of CVD. [Table: see text]
Healthy lifestyle, Agent Orange exposure, and inherited PCa risk: An analysis of the Million Veteran Program.
Authors: Meghana Pagadala, Asona Lui, Julie Ann Lynch, Roshan Karunamuni, Kyung Min Lee, Anna Plym, Brent S. Rose, Hannah Carter, Adam S. Kibel, Scott L. DuVall, J. Michael Gaziano, Matthew Panizzon, Richard Hauger, Tyler M Seibert
Journal: Journal of Clinical Oncology (2023)

210 Background: Prostate cancer (PCa) risk is understood to be mostly unmodifiable and inherited, but there is evidence that environmental and behavioral factors may also contribute. A recent study of health professional cohorts suggests a healthy lifestyle can mitigate a high inherited risk of lethal PCa. It is unknown how modifiable factors affect PCa risk in more diverse populations. Our objective was to determine the effects of healthy lifestyle and Agent Orange exposure on PCa risk when accounting for race/ethnicity, family history, and genetic risk in a diverse population. Methods: The Million Veteran Program (MVP) is a national, population-based cohort study of United States military veterans conducted 2011-2021 with 590,750 male participants available for analysis. Healthy lifestyle was quantified as: A healthy lifestyle score (range 0-3) was calculated with a point assigned for each of the following at MVP enrollment: not a current smoker, body mass index (BMI) 30 and strenuous activity 2 days per week. Agent Orange exposure was obtained from VA records. Genetic risk was assessed via a polygenic hazard score using genotype data. Results: Healthy lifestyle was independently associated with reduced metastatic PCa (HR 0.82, 95% CI 0.77–0.87, p&lt;0.001) and fatal PCa (HR 0.76, 95% CI 0.68–0.86, p&lt;0.01) when accounting for family history, genetic risk, and race/ethnicity. The benefit of healthy lifestyle was also observed in Black participants on subset analysis. Agent Orange exposure was an independent factor for PCa diagnosis (HR 1.06, 95% CI 1.04-1.09). Conclusions: Adherence to a healthy lifestyle is associated with reduced risk of metastatic or fatal PCa, which offsets inherited risk.
Patient characteristics and safety of radium-223 dichloride in Taiwan: Analysis of real-world clinical practice.
Authors: See-Tong Pang, Chao-Yuan Huang, Chi-Ping Huang, Yu-Yi Huang, Steven Kuan-Hua Huang, Kevin Lu, William J. Huang, En Meng, Shu-Pin Huang, Ming-Yang Lee
Journal: Journal of Clinical Oncology (2023)

119 Background: Bone metastases commonly develop in patients with metastatic castration-resistant prostate cancer (mCRPC), leading to poor clinical outcomes. Radium-223 (Ra-223) is a bone-targeting radiopharmaceutical that has been shown to improve the overall survival of these patients. Here, we present data on the safety and effectiveness of Ra-223 in patients with mCRPC and symptomatic bone metastases under routine clinical practice in Taiwan. Methods: This prospective, multicenter, single-arm, non-interventional observational study enrolled patients with mCRPC and symptomatic bone metastases. A total of 224 patients were included from July 2020 to January 2022. The patients received Ra-223 (55 kBq/kg of body weight) once every 4 weeks for a maximum of 6 intravenous injections. An exploratory subgroup analysis was conducted in patients who received Ra-223 either as a first-line, second-line or third-line. This first interim analysis of the study assessed the clinical outcomes observed during 6 months of Ra-223 treatment and 1 month after the final or last tolerated injection. Results: The dataset up until September 2021 (n = 104) was available for analysis. Of the 104 patients, 69 (66.3%) received 5–6 injections of Ra-223 while 35 (33.7%) received 1–4 injections. Sixty percent of enrolled patients were chemotherapy-naive. Furthermore, 22 (21.2%), 43 (41.3%) and 39 (37.5%) patients received Ra-223 as a first-, second- or third-line therapy, respectively; 16 (72.7%), 27 (62.8%) and 26 (66.7%) patients in these subgroups received 5–6 injections of Ra-223, respectively. The incidence of any study drug-related treatment-emergent adverse events (TEAEs), hematologic TEAEs and all fracture events were 10.6%, 9.6% and 1.9%, respectively. When compared with the other subgroups, patients on first-line Ra-223 therapy had lower incidences of any drug-related AEs and discontinuation of therapy owing to AEs. In addition, there was a trend observed that better PSA control occurred in patient population using Ra-223 as mCRPC first-line treatment. Conclusions: The study data showed that under routine clinical practice in Taiwan, the rate of Ra-223-associated AEs were low and no new safety concerns were identified with this therapy. First-line Ra-223 therapy was more likely associated with fewer TEAEs and higher rates of completion with the 6-injection course of therapy. A follow-up observation of up to 2 years after the initial injection is on-going. Clinical trial information: NCT04232761 .
Improved health-related quality of life (HR-QOL) with use of an online mindfulness tool in patients with metastatic renal cell carcinoma (mRCC) receiving immunotherapy (IO).
Authors: Cristiane Decat Bergerot, Jasnoor Malhotra, Paulo Gustavo Bergerot, Errol James Philip, Daniela V. Castro, Ameish Govindarajan, Lorena Nascimento Manrique Molina, William Hiromi Fuzita, Andressa Cardoso Azeredo, Augusto C. A. Mota, Marcos V S Franca, Gabriel dos Anjos, Romildo De Araujo Periera Filho, Douglas Manfroi de Souza, Joann Hsu, Neal Chawla, Alex Chehrazi-Raffle, Bechara Saab, Linda E Carlson, Sumanta Monty Pal
Journal: Journal of Clinical Oncology (2023)

660 Background: Previous randomized studies have shown the benefit of interventions to increase mindfulness in multiple cancer types, including prostate cancer (Chambers et al JCO 2017), but limited data exists in mRCC. We sought to determine the effect of an app-based mindfulness intervention on anxiety, fear of cancer progression (FCR), fatigue and HR-QOL in this population. Methods: Eligible patients had mRCC, were receiving IO, had measurable symptoms of anxiety or FCR, had a smartphone with internet access and had not participated in a mindfulness program in the past 5 years. Patients were recruited in Brazil across 7 private centers and one academic center in the US. We evaluated the Mindfulness-Based Cancer Survivorship Journey, a program within the Am Mindfulness smartphone app (AmDTx). Patients used AmDTx for 20-30 minutes each day for a minimum of 4 days per week over a period of 4 weeks. Patients were assessed at baseline (T1) and at weeks 2 (T2), 4 (T3) and 12 (T4) using the PROMIS-Anxiety, FCR-7, Brief Fatigue Inventory (BFI), and Functional Assessment of Chronic Illness Therapy-General (FACT-G). RM-ANOVA was used to test the effect of time on symptoms and on HR-QOL. Results: A total of 41 patients were recruited; median age was 59 (range, 36-79) and patients were predominantly male (70%), white (61%), married (75%) and well educated (65% had at least a college degree). Most patients were receiving nivolumab/ipilimumab (44%), nivolumab (22%) or axitinib/pembrolizumab (9%). Symptoms of anxiety significantly decreased from 21.6 + 4.8 to 12.5 + 5.1 (P=0.001). Similar findings were found for FCR (M T1 =21.4 to M T4 =13.5, P=0.001) and fatigue (M T1 =32.0 to M T4 =19.4, P=0.001). Notably, HR-QOL increased from 81.1 + 13.4 to 92.7 + 14.9 (P=0.001). No significant differences were identified based on disease characteristics or type of therapy. Conclusions: The current study suggests that smartphone-based mindfulness intervention could improve HR-QOL and decreased FCR, anxiety and fatigue. This low-cost, easily accessible intervention may provide an important alternative to in-person psychosocial support for patients with mRCC and should be assessed in randomized trials in this disease. Funding: Kure It Cancer Research: 2020 Barry Hoeven Memorial Kidney Cancer Research Grant (PI: C D Bergerot).
Real-world prostate-specific antigen (PSA) response and disease progression among patients with non-metastatic castration-resistant prostate cancer (nmCRPC) initiated on apalutamide (APA).
Authors: Benjamin H Lowentritt, Shawn Du, Carmine Rossi, Frederic Kinkead, Dexter Waters, Bronwyn Moore, Patrick Lefebvre, Dominic Pilon, Erik Muser
Journal: Journal of Clinical Oncology (2023)

69 Background: For patients with nmCRPC, APA with androgen deprivation therapy is an important therapeutic option with demonstrated efficacy in improving metastasis-free survival (MFS), and other clinical outcomes. However, there is limited real-world information on these outcomes among patients with nmCRPC treated with APA. This study describes PSA response and MFS among patients with nmCRPC treated with APA in the United States as compared to the SPARTAN registrational trial. Methods: Clinical data from 2/2017 to 4/2022 collected from 77 community-based urology practices were used to evaluate patients with nmCRPC who received ≥1 APA dispensation (index date being the date of first dispensation). Patients were excluded if they had previously used another next-generation antiandrogen or had &lt;12 months of pre-index clinical activity. PSA response was evaluated while on treatment and was defined as a post-index ≥90% decline (PSA90) in PSA from baseline (using the closest PSA value within 13 weeks prior to or on the index date) and was reported in patients with ≥1 post-index PSA test result by 3 months, 6 months, 12 months and overall. Disease progression was evaluated as MFS and defined as the time from index date to the occurrence of metastasis or death, whichever occurred first. Disease progression was described using Kaplan-Meier (KM) analysis by 6-month increments up to 24 months post-index. Results: A total of 406 patients with nmCRPC (mean age 78.8 years, 73% white, mean baseline PSA 9.0 ng/mL) were identified. Among 96 patients with available data, the mean (median) baseline PSA doubling time was 9.9 (7.5) months. The mean (median) treatment duration was 434 (305) days. PSA90 rates were 40% by 3 months, 51% by 6 months, 56% by 12 months, and 58% overall. KM rates for MFS were 95% at 6 months, 90% at 12 months, 82% at 18 months, and 75% at 24 months. PSA response and MFS for real-world patients were consistent with those observed from the SPARTAN trial. Conclusions: This real-world study of patients with nmCRPC demonstrates that APA treatment resulted in early, deep PSA responses, consistent with the SPARTAN trial. Moreover, MFS observed in the real-world was similar to that of the SPARTAN trial. [Table: see text]
Correlation of the immune tumor microenvironment (I-TME) with gene expression profiles as prognostic and predictive factors in patients (pts) with metastatic renal carcinoma (mRCC) treated with immunotherapy (Meet-URO 18 I-TME study).
Authors: Fabio Catalano, Veronica Murianni, Sara Elena Rebuzzi, Francesca Galuppini, Sebastiano Buti, Matteo Brunelli, Marco Maruzzo, Angelo Paolo Dei Tos, Umberto Basso, Giuseppe Lugi Banna, Alessio Signori, Marta Sbaraglia, Alessandra Damassi, Malvina Cremante, Silvia Puglisi, Annalice Gandini, Marta Rebuzzi, Alessandra Mosca, Giuseppe Fornarini, Pasquale Rescigno
Journal: Journal of Clinical Oncology (2023)

TPS753 Background: Several studies suggested that response to immunotherapy may be influenced by many factors, including peripheral blood biomarkers, the composition of I-TME and different molecular expression pathways. In mRCC patients, immunotherapy has become part of clinical practice, but the identification of patients most likely to respond to checkpoint inhibitors is still an unmet clinical need. Moreover, there are no validated and clinically applicable gene expression panels as prognostic and/or predictive response biomarkers. To date, three major groups of immune-related gene expression were identified in mRCC: the angiogenesis pathway, the T-effector pathway and the mixed pathway (doi: 10.1038/s41598-020-58804-y). Each group of gene expression seems to be responsible for a different type of immune response in the I-TME. However, a significant association with treatment response to immunotherapy has not yet been demonstrated. Methods: The Meet-URO 18 is a multicentric retrospective translational study aimed at identifying distinctive molecular patterns of the I-TME with a prognostic and predictive role in mRCC (primary objective). Pretreated mRCC patients receiving ≥2 nd line nivolumab have been divided according to clinical benefit in responders (PFS ≥ 12 months) versus non-responders (PFS ≤ 3 months). Secondary objectives include the correlation between primary tumor and metastases to identify a potential inter-tumor heterogeneity and the correlation with survival and response outcomes. Histological samples of primary tumors and/or metastases have been collected for the transcriptomic analyses together with clinical data of patients from medical records. The transcriptomic characterization of the I-TME of the primary tumor and/or metastases will be performed using the analytical platform "nCounter" of NanoString®, which analyzes the expression of 71 genes involved in angiogenesis, immunomodulation mediated by T-effector response, mechanisms of tumor invasion and mechanisms of calcium channel flows. The gene-panel include a group of 66 genes previously demonstrated to be related in the immune-response in mRCC (doi: 10.1038/s41598-020-58804-y) and 5 housekeeping genes (RPS13, PPIA, RPL27, RP2, B-ACT).
Response and outcomes of maintenance avelumab after platinum-based chemotherapy (PBC) in patients (pts) with advanced urothelial carcinoma (aUC): "Real world" experience.
Authors: Dimitra Rafailia Bakaloudi, Rafee Talukder, Dimitrios Makrakis, Neeraj Agarwal, Nishita Tripathi, Aristotelis Bamias, Roubini Zakopoulou, Jason Brown, James Korolewicz, Claudia A.M. Fulgenzi, Tanya Jindal, Jure Murgic, Ana Fröbe, Jeffrey Johnson, Alexandra Drakaki, Alejo Rodríguez-Vida, Macarena Rey-Cárdenas, Lucia Andrea Alonso Buznego, Ali Raza Khaki, Petros Grivas
Journal: Journal of Clinical Oncology (2023)

472 Background: PBC followed by avelumab switch maintenance in non-progressors is the standard first line (1L) aUC treatment. We describe clinical features and outcomes in a ‘real-world’ cohort treated with avelumab maintenance for aUC. We hypothesized that outcomes would be similar with JavelinBladder100 trial data. Methods: This was a retrospective cohort study of pts from 12 sites who received 1L switch maintenance avelumab after no progression to PBC for aUC. We calculated overall response rate (ORR), median overall and progression-free survival (mOS, mPFS) using Kaplan Meier method from avelumab start. We also described OS and PFS for specific subsets using Cox regression. Results: We found 77 pts with aUC (78% pure, 22% mixed UC) with median age 68, 81% men, 91% White, 17% upper tract primary, 66% prior cisplatin, 17% liver metastasis (mets), 80% ECOG PS 0-1 at time of PBC start. There was a median of 6 weeks (range 1-30) from end of PBC to avelumab start; median follow-up time from avelumab start was 22 months (95%CI 16-24). ORR with avelumab maintenance: 28% (complete response [CR] 17%, partial response [PR] 11%), stable disease (SD) 32%; progression as best response 30% (10% unknown); mPFS 7 months (95%CI 5-9), mOS 22 months (95%CI 16-NR). Table shows HR for OS and PFS for specific subsets. Absence (vs presence) of liver mets (p=0.04), ECOG PS 0-1 (vs &gt;1; p=0.01) and CR/PR (vs SD) to 1L PBC (p=0.03) were associated with longer OS. Conclusions:‘Real world’ outcomes with avelumab maintenance in pts with aUC align with JavelinBladder100 trial data (but higher ORR). Good PS, response to PBC and absence of liver mets are favorable prognostic factors. Limitations include moderate sample size, retrospective design, lack of randomization and central scan review, possible selection and confounding biases. Other studies (e.g. PATRIOT-II) can generate more data in pts on maintenance avelumab outside clinical trials. [Table: see text]